CN101580524A - Method for preparing digalactosyldiacylglycerol and application thereof - Google Patents

Method for preparing digalactosyldiacylglycerol and application thereof Download PDF

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Publication number
CN101580524A
CN101580524A CNA2009100117508A CN200910011750A CN101580524A CN 101580524 A CN101580524 A CN 101580524A CN A2009100117508 A CNA2009100117508 A CN A2009100117508A CN 200910011750 A CN200910011750 A CN 200910011750A CN 101580524 A CN101580524 A CN 101580524A
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silica gel
dgdg
acetone
preparation
chloroform
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陈大为
赵庆春
李新刚
胡海洋
赵秀丽
乔明曦
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Shenyang Pharmaceutical University
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Shenyang Pharmaceutical University
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    • Y02P20/00—Technologies relating to chemical industry
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Abstract

The invention relates to a method for preparing a pharmaceutical natural surfactant, namely digalactosyldiacylglycerol (DGDG) and application thereof as a pharmaceutical carrier. The preparation technology thereof comprises the following steps: using acetone to extract oat bran, concentrating a leaching liquor and absorbing the concentrated leaching liquor by silica gel, using different polarities of eluents to elute the silica gel respectively, and finally obtaining refined DGDG in the eluents; or using carbon dioxide to supercritically degrease the oat bran first, then using the acetone for extraction, using the silica gel to absorb after an extracting solution is concentrated, and obtaining the refined DGDG after different polarities of eluents are used for elution. The hydrophile-lipophile balance value of the DGDG is between 7.00 and 8.15, and the critical micelle concentration is about 2*10<-3>g.L<-1>. The preparation method has cheap and easily-obtained raw materials, and the obtained DGDG is thin-layer chromatographically pure and has no hemolyticity and irritation. The DGDG has amphipathy, and can self-assemble to form double-layer vesicles in water, so that the DGDG can be taken as the pharmaceutical carrier. Galactose residues in DGDG molecules can be taken as a ligand, specifically identify galactose receptors on hepatic parenchymal cells, and realize ligand mediated active liver target.

Description

The preparation method of digalactosyl diacylglycerol and application thereof
Technical field
The invention belongs to the preparation and the applied technical field of medicinal natural surface active agent, relate to the preparation method and the application thereof of digalactosyl diacylglycerol, be specifically related to the initiatively application of target medicine carrier of its preparation method and conduct thereof.
Background technology
In digalactosyl diacylglycerol (DGDG) molecule, exist a DG and two galactose residues connected to one another, first galactose residue directly links to each other with C-3 position-OH group on the glycerol backbone.Second galactose residue and first semi-lactosi connect with α-1,6 glycosidic link, wherein, and R 1, R 2Be different types of lipid acid, in the glycolipid that extracts by oat bran, mostly be palmitinic acid (C 15H 31CO; 16:0), oleic acid (C 17H 33CO; 18:1), linolic acid (C 17H 31CO; 18:2), a spot of linolenic acid (C is also arranged 17H 29CO; 18:3), stearic acid (C 17H 35CO; 18:0), lauric acid (C 11H 23CO; 12:0) etc.DGDG is not a kind of pure substance, but one group of mixture that structure is close, its structure such as Fig. 1.From its structure, the hydroxyl of galactose units and semi-lactosi acylglycerol are hydrophilic radical, and the fat chain is a lipophilic group, and it is significantly amphipathic that this makes that galactolipid has, and are a kind of natural nonionic surface active agent.The method of producing galactolipid is open report in patent CN1144478A, and it is an extraction separation and get from oatmeal, wheat gluten, rye meal, uses extraction using alcohol, the silicagel column separation, and elutriant is respectively hexane and the Virahol and the acetone of different ratios.The main drawback of its method is: the raw materials used grain that is, and cost is higher; Extracted more impurity component in the ethanol extract, for next step separation and purification has increased difficulty; Finally by still having impurity among the refining gained DGDG of acetone elutriant.DGDG's is amphipathic, and make it can be used as surfactant and use, because the similar frustum of a cone of its molecule, can spontaneous formation bilayer in water, and then form lipoid plastid or vesica.Based on above 2 points, DGDG can be used as medicine, nutritious prod, and the solid support material of makeup, food, agricultural supplie uses.Yet with its as in the solid support material of pharmaceutically active substance do not appear in the newspapers.
Summary of the invention
The purpose of this invention is to provide a kind of low cost and more purified DGDG extraction and separation method.Extract impurity is few, and the refining DGDG that obtains is that thin-layer chromatography is pure, nonirritant and hemolytic, and with its as in the solid support material of pharmaceutically active substance.
The present invention is achieved in that and contains more lipid composition in the oat bran, so select wheat bran for use without the higher oatmeal of cost; Less by the extract obtained middle impurity of acetone; Separate by twice silicagel column, last silicagel column adopts resolution chloroform-methanol system wash-out preferably, separates obtaining purified DGDG.
Its step of preparation process is:
Get oat bran,, extracted 2～4 hours under 40～56 ℃ with 2～4 times of amounts (w/v) acetone, lixiviate 3 times merges vat liquor.40～50 ℃ of following concentrating under reduced pressure of vat liquor, the gained brown oil is with 2～3 times of amounts (w/w) silica gel mixed sample.Elder generation adds and mixes the blank silica gel of sample silica gel equivalent in separator column, the back adds mixes sample silica gel, use 10～30: 90～70 (v/v) of hexanaphthene-acetone to mix the elutriant wash-out then, consumption is 2～4 times (w/w) of total silica gel consumption in the post, use the acetone wash-out at last, consumption is 2.5～5 times (w/w) of total silica gel consumption in the post.40～50 ℃ of following concentrating under reduced pressure of acetone elutriant, the yellow thickness paste of gained is rough DGDG, with it with 1～3 times of amount (w/w) silica gel mixed sample.In separator column, add and mix the blank silica gel of 2～4 times of amounts of sample silica gel (w/w), the back adds mixes sample silica gel, use 70～90: 30～10 (v/v) mixed solution wash-out of chloroform-methanol then, consumption is 4～8 times (v/w) of total silica gel amount in the post, use 60～80: 40～20 (v/v) mixed solution wash-out of chloroform-methanol at last, consumption is 5～10 times (v/w) of total silica gel amount in the post.Be refining DGDG in 60～80: 40～20 (v/v) elutriant of chloroform-methanol.
Also oat bran can be carried out degreasing with CO 2 supercritical, extraction kettle pressure is 29.0～31.2MPa, and the extraction kettle temperature is 35～45 ℃, and dividing a temperature is 40～60 ℃, and dividing two temperature is 20～40 ℃, and flow system flow is 70～83Kgh -1Oat bran after the degreasing, extracted 2～4 hours under 40～56 ℃ with 2～4 times of amount acetone, and lixiviate 3 times merges vat liquor.40～50 ℃ of following concentrating under reduced pressure of vat liquor, concentrated solution is with 1～3 times of amount (w/w) silica gel mixed sample.In separator column, add and mix the blank silica gel of 2～4 times of amounts of sample silica gel (w/w), the back adds mixes sample silica gel, use 70～90: 30～10 (v/v) mixed solution wash-out of chloroform-methanol then, consumption is 4～8 times (v/w) of total silica gel amount in the post, use 60～80: 40～20 (v/v) mixed solution wash-out of chloroform-methanol at last, consumption is 5～10 times (v/w) of total silica gel amount in the post.Be refining DGDG in 60～80: 40～20 (v/v) elutriant of chloroform-methanol.
Gained DGDG launches with silica gel thin-layer, and developping agent is chloroform-methanol-water mixed solvent, and thin layer plate volatilizes the developer aniline-pentanoic phosphoric acid of back left side spray sugar, and general developer 10% ethanol solution of sulfuric acid is sprayed on the right side, 85 ℃ of heating colour developings in 10 minutes down, as Fig. 2:
Gained DGDG launches with silica gel thin-layer, and developping agent is chloroform-acetone-acetate mixed solvent, and thin layer plate volatilizes the developer aniline-pentanoic phosphoric acid of right side, back spray sugar, and general developer 10% ethanol solution of sulfuric acid is sprayed in the left side, 85 ℃ of heating colour developings in 10 minutes down, as Fig. 3:
By contrasting as seen: the DGDG that carries is comparatively pure in institute, does not detect impurity in thin layer plate.
With gained DGDG 1molL -1HCl was in 75 ℃ of following hydrolysis 1 hour, be total to thin-layer developing with the semi-lactosi standard substance, developping agent is respectively ethyl acetate-methyl alcohol-acetate-water=12: 3: 3: 2, chloroform-methanol-water=70: 21: 3, chloroform-methanol-water=16: 9: 2, thin layer plate volatilizes back spray developer aniline-pentanoic phosphoric acid, 85 ℃ of heating colour developings in 5 minutes down, and the result is respectively as Fig. 4, Fig. 5, Fig. 6.As seen from the figure: Rf is identical under three kinds of developping agents, illustrates that gained is a semi-lactosi after the hydrolysis.
Gained DGDG sample H 1-NMR (mark in the Bruker AX-300 type nuclear magnetic resonance spectrometer, TMS) is as Fig. 7.
Use the NMR method and record HLB value such as Table 1:
HLB＝18.24R+1.80
Table?1?The?result?of?HLB?value?determination
The micelle-forming concentration that application fluorescent probe method records DGDG is 2 * 10 -3GL -1
The safety evaluation of DGDG
1, hemolytic test
Record the result by " technical director's principle of Chinese medicine, natural drug pungency and hemolytic research ", the 1.5%DGDG aqueous solution does not have haemolysis.
2, irritation test (rabbit ear hypodermic injection)
Get two rabbit, the hair in the middle part of its two ear is taken off, the left ear middle part tested thing of subcutaneous injection (1.5% the DGDG aqueous solution) 0.1mL, auris dextra middle part subcutaneous injection equivalent physiological saline.Observe injection site and have or not red and swollen and congested phenomenon, and contrast, nonirritant is arranged with judgement sample with the physiological saline group.
Each time point observations such as Table 2
Table?2?The?results?of?stimulation?test
Figure A20091001175000051
By irritation test proof DGDG nonirritant.
Owing to contain ester bond and unsaturated double-bond among the DGDG, should be enclosed within the low temperature (4 ℃) and preserve.
The prepared DGDG impurity of the present invention is few, and the refining DGDG that obtains is that thin-layer chromatography is pure, nonirritant and hemolytic, and the solid support material of pharmaceutically active substance in can be used as.
Description of drawings:
Fig. 1 is the molecular structure of DGDG
Fig. 2 is the thin-layer chromatogram that launches back DGDG with chloroform-methanol-water
Fig. 3 is the thin-layer chromatogram that launches back DGDG with chloroform-acetone-acetate
Fig. 4 is the thin-layer chromatogram that launches acid hydrolysis DGDG with ethyl acetate-methyl alcohol-acetate-water
Fig. 5 is the thin-layer chromatogram that launches acid hydrolysis DGDG with chloroform-methanol-water (70: 21: 3)
Fig. 6 is the thin-layer chromatogram that launches acid hydrolysis DGDG with chloroform-methanol-water (16: 9: 2)
Fig. 7 is the H of DGDG 1-NMR spectrogram
Fig. 8 is Oleum Pelargonii Graveolentis submicron emulsion particle diameter and distribution plan thereof
Fig. 9 is the HPLC color atlas behind the cucurbitacine liposome purifying
The tissue distribution figure of cucurbitacine liposome when Figure 10 is 30min
The tissue distribution figure of cucurbitacine liposome when Figure 11 is 1h
The tissue distribution figure of cucurbitacine liposome when Figure 12 is 2h
The tissue distribution figure of cucurbitacine liposome when Figure 13 is 4h
Embodiment
Embodiment 1: acetone extraction-silicagel column separates DGDG
Take by weighing commercially available oat bran 500g and add 1120mL acetone in 56 ℃ of following lixiviates 4 hours, lixiviate 3 times merges 3 times vat liquor.Vat liquor is in 50 ℃ of following concentrating under reduced pressure, and concentrated solution is mixed thoroughly with 100g silica gel, volatilizes solvent.Add the blank silica gel of 110g in separator column, the back adds mixes sample silica gel.Elder generation uses acetone 900mL wash-out at last with the mixed solution 680mL wash-out of 28: 72 (v/v) of hexanaphthene-acetone.The acetone elutriant is in 47 ℃ of following concentrating under reduced pressure, and enriched material 30g silica gel mixed sample volatilizes solvent.Add the blank silica gel of 100g in separator column, the back adds mixes sample silica gel.With 85: 15 (v/v) mixed solution wash-outs of 650mL chloroform-methanol, at last with 70: 30 (v/v) mixed solution wash-outs of 680mL chloroform-methanol, 70: 30 (v/v) reclaiming chloroform-methanol mixes elutriant earlier, and gained is refining DGDG.
Embodiment 2: CO 2 supercritical degreasing-extraction separation DGDG
Take by weighing commercially available oat bran 500g, put into the extraction kettle of carbon dioxide upercritical fluid extraction equipment, extracting pressure 31MPa is set, 42 ℃ of extraction temperature, separator one temperature is 48 ℃, and separator two temperature are 25 ℃, and flow system flow is for being controlled at 75～78Kgh -1, access extract per half an hour in separator one, coextraction 3 hours.Take out the oat bran after extracting, in 50 ℃ of following lixiviates 2.5 hours, lixiviate 3 times merged 3 times vat liquor with 1200mL acetone.Vat liquor is in 45 ℃ of following concentrating under reduced pressure.Concentrated solution 25g silica gel mixed sample volatilizes solvent.Add the blank silica gel of 85g in separator column, the back adds mixes sample silica gel.With 85: 15 (v/v) mixed solution wash-outs of 700mL chloroform-methanol, at last with 70: 30 (v/v) mixed solution wash-outs of 750mL chloroform-methanol, 70: 30 (v/v) reclaiming chloroform-methanol mixes elutriant earlier, and gained is refining DGDG.
Embodiment 3: the preparation of Oleum Pelargonii Graveolentis DGDG submicron emulsion
Take by weighing DGDG0.8g, Oleum Pelargonii Graveolentis 2g, sodium oleate 0.1g, 50 ℃ of down insulations add 100mL (50 ℃) water for injection behind the vortex mixing, are stirred to into homogeneous emulsion, it is sheared 5min with tissue refiner after, it is even to go into the high pressure breast, pressure 750bar, even matter 5 times, promptly.Median size 222.2nm, size distribution is narrower.See Fig. 8.
Embodiment 4: the preparation of cucurbitacin DGDG lipoid plastid
Take by weighing DGDG75mg, cholesterol 8mg, cucurbitacin 4mg, the rotary evaporation that reduces pressure in the eggplant-shape bottle is poured in an amount of chloroform dissolving into, form film after, pour phosphate buffered saline buffer into, ultra-sonic dispersion is crossed twice of 0.45 μ m filter membrane promptly.Gained preparation microtrabeculae centrifuging purifying is removed free cucurbitacin.So purifying preparation Virahol destroys, advance HPLC and analyze, can detect cucurbitacin medicine peak.See Fig. 9.
Embodiment 5: the tissue distribution of cucurbitacin DGDG lipoid plastid
By implementation method four preparation preparations, prepare the cucurbitacin aqueous solution that content of dispersion equates simultaneously, in contrast.Wistar rat male and female half and half, body weight 200 ± 20g.The tissue distribution assays method is measured 30min respectively routinely, 1h, 2h, the tissue distribution during 4h, result such as Figure 10,11,12,13.

Claims (9)

1. the preparation method of digalactosyl diacylglycerol is characterized in that: adopt the following steps preparation:
Get the oat bran acetone extraction, the vat liquor concentrating under reduced pressure, the gained brown oil is adsorbed with 2～3 times of amounts (w/w) silica gel mixed sample.Add earlier blank silica gel in separator column, the back adds mixes sample silica gel, blank silica gel: mix sample silica gel=2～4: 1 (w/w), use 10～30: 90～70 (v/v) mixed solution wash-out of hexanaphthene-acetone then, and use the acetone wash-out at last; Acetone elutriant concentrating under reduced pressure, gained thickness paste is inhaled with 1～3 times of amount (w/w) silica gel mixed sample, in separator column, add blank silica gel earlier, the back adds mixes sample silica gel, blank silica gel: mix sample silica gel=2～4: 1, use 70～90: 30～10 (v/v) mixed solution wash-out of chloroform-methanol then, use 60～80: 40～20 (v/v) mixed solution wash-out of chloroform-methanol at last, be refining DGDG in 60～80: 40～20 (v/v) the mixing elutriant of chloroform-methanol;
Or oat bran carried out degreasing with carbon dioxide upercritical fluid extraction, and the oat bran acetone extraction after the degreasing, the vat liquor concentrating under reduced pressure adsorbs with 1～3 times of amount (w/w) silica gel mixed sample.In separator column, add blank silica gel earlier, the back adds mixes sample silica gel, blank silica gel: mix sample silica gel=2～4: 1 (w/w), use 70～90: 30～10 (v/v) mixed solution wash-out of chloroform-methanol then, use 60～80: 40～20 (v/v) mixed solution wash-out of chloroform-methanol at last, be refining DGDG in 60～80: 40～20 (v/v) the mixing elutriant of chloroform-methanol.
2, preparation method according to claim 1, it is characterized in that: carbon dioxide upercritical fluid extraction still pressure is 29.0～31.2MPa, and the extraction kettle temperature is 35～45 ℃, and separator one temperature is 40～60 ℃, separator two temperature are 20～40 ℃, and flow system flow is 70～83Kgh -1
3, preparation method according to claim 1 is characterized in that: oat bran is with in the acetone extraction, and used acetone consumption is 2～4 times (v/w) of oat bran, and extracting temperature is 40～56 ℃, and 2～4 hours extraction times, lixiviate 3 times merges vat liquor.
4, preparation method according to claim 1 is characterized in that: it is 2～4 times (v/w) of the total consumption of silica gel in the post that 10～30: 90～70 (v/v) of hexanaphthene-acetone mix the elutriant consumption.
5, preparation method according to claim 1 is characterized in that: acetone elutriant consumption is 2.5～5 times (v/w) of the total consumption of silica gel in the post.
6, preparation method according to claim 1 is characterized in that: it is 4～8 times of total silica gel amount in the post that 70～90: 30～10 (v/v) of chloroform-methanol mix the elutriant consumption; It is 5～10 times (v/w) of the total consumption of silica gel in the post that 60～80: 40～20 (v/v) of chloroform-methanol mix the elutriant consumption.
7, preparation method according to claim 1, it is characterized in that: prepared digalactosyl diacylglycerol can be made emulsion and lipoid plastid with pharmaceutically acceptable carrier combination, the digalactosyl diacylglycerol that wherein contains 0.01～30% (w/w), all the other are middle pharmaceutically active substance, polar solvent and other auxiliary material.
8, preparation method according to claim 1 is characterized in that: the galactose residue of prepared digalactosyl diacylglycerol can be used as part, has liver target.
9, according to claim 7 or 8 described preparation methods, it is characterized in that: in the emulsion and lipoid plastid that prepared digalactosyl diacylglycerol is made, its route of delivery comprises: subcutaneous, muscle and vein.
CNA2009100117508A 2009-05-27 2009-05-27 Method for preparing digalactosyldiacylglycerol and application thereof Pending CN101580524A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101787059A (en) * 2009-05-12 2010-07-28 沈阳药科大学 Method for preparing digalactosyl diacylglycerol and application thereof
CN110183500A (en) * 2019-07-05 2019-08-30 湖北中医药大学 A kind of preparation method of plant galactolipid

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101787059A (en) * 2009-05-12 2010-07-28 沈阳药科大学 Method for preparing digalactosyl diacylglycerol and application thereof
CN101787059B (en) * 2009-05-12 2014-10-15 沈阳药科大学 Method for preparing digalactosyl diacylglycerol and application thereof
CN110183500A (en) * 2019-07-05 2019-08-30 湖北中医药大学 A kind of preparation method of plant galactolipid

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Application publication date: 20091118